1. ¹Department of Pathology, New York University, New York, NY, USA
2. ²Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
4. ⁴Department of Surgery and Department of Human Genetics, McGill University and Genetics Unit, Shriners Hospital for Children, Montréal, Québec, Canada

Correspondence: Dr JL Sepulveda, MD, PhD, Department of Pathology, University of Pittsburgh, CHP MT 5835, 200 Lothrop, Pittsburgh, PA 15213, USA. E-mail: sepulvedajl@upmc.edu

Received 17 September 2004; Revised 19 July 2005; Accepted 20 July 2005; Published online 19 September 2005.

Abstract

Outside-in signaling from fibronectin (FN) through integrin receptors has been shown to play an important role in promoting cardiac myocyte hypertrophy and synergizes with other hypertrophic stimuli such as the alpha-adrenergic agonist phenylephrine (PE) and mechanical strain. The integrin-linked kinase (ILK) is a critical molecule involved in cell adhesion, motility and survival in nonmyocytes such as fibroblasts and epithelial cells. Its role in cardiac myocytes is unclear. In this study, we demonstrate that (1) ILK forms a complex with PINCH1 and alpha-parvin proteins (IPAP1 complex) in neonatal rat ventricular myocytes; (2) localization of IPAP1 complex proteins to costameres in cardiac myocytes is stimulated by FN, PE and synergistically by the combination of FN and PE in an integrin 1-dependent manner; (3) a dominant-negative mutant lacking the PINCH-binding N-terminus of ILK (ILK-C) prevents costamere association of ILK and alpha-parvin, but not PINCH1; (4) FN- and PE-induced hypertrophy, measured by increased protein/DNA ratio, beating frequency and atrial natriuretic peptide expression, is stimulated by low levels of ILK-C but repressed by high ILK-C expression; and (5) overexpression of ILK-C, as well as deletion of the ILK gene in mouse neonatal ventricular myocytes, induces marked apoptosis of cardiac myocytes. These results suggest that the IPAP1 complex plays an important role in mediating integrin-signaling pathways that regulate cardiac myocyte hypertrophy and resistance to apoptosis.